Arylthioureido pyridinecarbamino compounds and use as plant growth regulants

ABSTRACT

A method of regulating the growth of plants, including combating unwanted vegetation, comprises applying to the plants, either on seed, the soil or directly on the plants an effective amount of a novel compound of the class having the general structural formula ##STR1## in which one of Q 1 , Q 2 , Q 3  or Q 4  is N, X is --OH or --O--(C 1  -C 4  alkyl) and Y is H or X and Y together represent a bond between carbon and nitrogen atoms and R is H or one or two of the following substituents: --Br, --Cl, --F, --I, --CF 3 , --CH 3 , --NO 2  or --C.tbd.N, or an agriculturally acceptable salt thereof.

This is a division of application Ser. No. 101,654 filed Dec. 10, 1979.

DESCRIPTION OF THE INVENTION

Many chemical substances have been found to have growth regulating effects on plants. Change of shape of plants, crinkling and folding of leaves, stunting of growth, defoliation, stimulation of root growth on cuttings and other effects are frequently observed. It is usually necessary to apply growth regulating substances to plants at comparatively low rates in order to have the growth regulating effects clearly evident. At higher rates a selective kill of vegetation is usually obtained, as some species of plants are effected more than others. Growth regulants have, in fact been used more as selective herbicides than for other purposes because in many instances the growth regulating effects exhibited by these substances have no other practical utility. However, a class of growth regulant compounds has now been discovered that produces a number of useful effects, differing from one plant species to another. For example, some of these compounds promote tillering (branching at the base of the plant) in oats and other grains and increase of fruit set in certain other plants.

Briefly, the class of growth regulant compounds has the general structural formula ##STR2## in which one of Q₁, Q₂, Q₃ or Q₄ is N, X is --OH or --O--(C₁ -C₄ alkyl) and Y is H or X and Y together represent a bond between carbon and nitrogen atoms and R is H or one or two of the following substituents: --Br, --Cl, --F, --I, --CF₃, --NO₂ or --C.tbd.N, including agriculturally acceptable salts thereof. Acceptable salts include amine salts and metallic salts of a carboxy substituent, as well as salts with the basic heterocyclic nitrogen atom and isothuronium salts. It will be understood that salts which leave toxic heavy metal residues are not agriculturally acceptable.

Synthesis of the Growth Regulants

The growth regulants may be synthesized according to the following general scheme: ##STR3## Below are specific illustrative procedures.

(All temperatures in the following procedures are °C.)

Preparation of 1-(3'-Carboxy-2'-pyridinecarbonyl)-2-methyl-4-phenyl-3-thiosemicarbazide

To a suspension of 4.5 g (0.03 mole) of pyridine-2,3-dicarboxylic anhydride in 100 ml chloroform was added 5.4 g (0.03 mole) of 2-methyl-4-phenyl-3-thiosemicarbazide. The resulting reaction mixture was allowed to stir at room temperature overnight. After filtering and drying there was obtained 9.3 g of the desired product, mp: 152°-153°. The IR and NMR spectra were consistent with the proposed structure.

Preparation of 1-(2'-Carbomethoxy-3'-pyridinecarbonyl)-2-methyl-4-phenyl-3-thiosemicarbazide

A suspension of 4.5 g (0.025 mole) of 2-carbomethoxy-3-pyridine carboxylic acid in 75 ml of thionyl chloride containing a few drops of dimethylformamide was refluxed until solution occurred. Evaporation gave 4.9 g of a brown oil consisting of crude ester-acid chloride which was used without further purification.

To a solution of 4.4 g (0.0245 mole) of 2-methyl-4-phenyl-thiosemicarbazide in 50 ml of dimethoxyethane containing 2.0 g (0.0245 mole) of pyridine cooled in -35° was added dropwise a solution of the above ester-acid chloride dissolved in 25 ml of dimethoxyethane. After complete addition the reaction mixture was allowed to come to room temperature and stirred overnight. The reaction mixture was then added to ice water and extracted with ethyl acetate. The organic layer was dried and evaporated to give a gummy residue which was crystallized from ether-ethyl acetate. There was obtained 3.2 g of the desired product, mp: 128°-129°. The IR and NMR spectra were consistent with the proposed structure.

Preparation of N-(1-Methyl-3-phenylthioureido)-2,3-pyridine-carboximide

To a suspension of 6.6 g (0.02 mole) of 1-(3'-carboxy-2'-pyridinecarbonyl)-2-methyl-4-phenyl-3-thiosemicarbazide in 150 ml of dimethoxyethane was added dropwise 4.1 g (0.02 mole) of dicyclohexylcarbodiimide in 50 ml of dimethoxyethane. The resulting yellow solution was allowed to stir at room temperature overnight. The precipitated dicyclohexylurea was removed by filtration and the yellow filtrate was evaporated almost to dryness. Isolation of the solid gave 2.3 g of the desired product, mp: 207°-210°. The IR and NMR spectra were consistent with the proposed structure.

In the following table there are listed novel compounds which have been made by means of the general procedures which are illustrated above.

    ______________________________________                                          ##STR4##                                                                      Com-                                                                           pound                                                                          No.    Q        X        Y    R        mp (°C.)                         ______________________________________                                         4167   Q.sub.1 = N                                                                             OH       H    2-F      152-153                                 4166                          4-CH.sub.3                                                                              148-149                                 4165                          3-Br     143-145                                 4051                          4-Cl     154-156                                 4004                          3,4-di Cl                                                                               157-159                                 4003                          3-CH.sub.3                                                                              152-154                                 4002                          2,4-dimethyl                                                                            149-154                                 4001                          3,4-dimethyl                                                                            155-161                                 3999                          3-Cl     143-144                                 3998                          4-CH.sub.3                                                                              165-168                                 3997                          3-CF.sub.3                                                                              141-142                                 3996                          3,5-di Cl                                                                               156-157                                 3970                          4-NO.sub.2                                                                              152-156                                 3925                          4-F      143- 145                                3924                          3-Cl-2-CH.sub.3                                                                         149-150                                 3923                          2-Cl     150-151                                 4228                          4-CN     165-168                                 4227                          2,4-di Cl                                                                               139-141                                 4226                          4-Br     144-147                                 4225                          4-I      148-149                                 3595                          H        149-151                                 4170   Q.sub.1 = N                                                                             X+Y is CN   2-F      147-154                                                   bond                                                           4169                        4-CF.sub.3                                                                              173-177                                   4168                        3-Br     156-162                                   4164                        3,4-di Cl                                                                               162-165                                   4163                        3-CH.sub.3                                                                              175-182                                   4162                        3,4-dimethyl                                                                            142-151                                   4157                        3-Cl     gum                                       4156                        4-CH.sub.3                                                                              148-159                                   4155                        3-CH.sub.3                                                                              gum                                       4154                        3,5-di Cl                                                                               178-184                                   4148                        4-NO.sub.2                                                                              198-203                                   4147                        3-Cl2-CH.sub.3                                                                          gum                                       4146                        2-Cl     gum                                       4106                        4-F      172-176                                   4096   Q.sub.4 = N                                                                             OCH.sub.3                                                                               H    4-F      142-145                                 4095                          3-Cl     103-111                                 4094                          4-CH.sub.3                                                                              96-102                                  4093                          3-CF.sub.3                                                                              111-114                                 4092                          3,5-di Cl                                                                               159-161                                 4091                          3,4-di Cl                                                                               gum                                     4090                          3-CH.sub.3                                                                              gum                                     4089                          2,4-dimethyl                                                                            72-86                                   4088                          3,4-dimethyl                                                                            65-78                                   3817                          H        128-129                                 3968   Q.sub.1 = N                                                                             OH       H    2-CH.sub.3                                                                              159-160                                 3969                          3-F      148-153                                 3984                          H        148-151                                 4149            X + Y is CN H        172-175                                                   bond                                                           3600   Q.sub.3 = N                                                                             OH       H    H        200 (dec)                               3818   Q.sub.2 = N                                                                             OCH.sub.3                                                                               H    H        162-169                                 3848   Q.sub.2 = N                                                                             X + Y is CN H        gum                                                       bond                                                           4098   Q.sub.4 = N                                                                             OCH.sub.3                                                                               H    H        106-115                                 ______________________________________                                    

Use of the Growth Regulants

By application of an effective amount of the growth regulants, either pre- or post-emergently, various effects on young plants become apparent. These effects may be demonstrated by means of the following illustrative procedures.

Pre-emergent Application

Disposable paper trays about 21/2 inches deep which were filled with soil were sprayed with aqueous spray mixtures at a rate of 10 lb. of active chemical per acre of sprayed area, then were seeded with 6 species of plant seeds and were covered with about 1/4 inch of soil. The spray mixtures were prepared by dissolving the proper amount of growth regulant compound in 15 ml of acetone, adding 4 ml of a solvent-emulsifier mixture consisting of 60 wt. percent of a commercial polyoxyethylated vegetable oil emulsifier (96 wt. percent active ingredient, Emulphor EL-719), 20 wt. percent xylene and 20 wt. percent deodorized kerosene, then bringing total volume up to 60 ml by addition of warm water. Twenty-one days after seeding and treatment the plantings were examined and plant injury was rated according to the following schedule.

DEGREE OF EFFECT

0=no effect

1=slight effect, plants recovered

2=moderate effect, injury to 26 to 75 percent

3=severe effect, injury to 76 to 99 percent of foliage

4=maximum effect (all plants died)

Post-emergent Application

Several species of plants were grown in potting soil in disposable styrofoam trays and tomatoes were grown in four-inch pots in the greenhouse. Aqueous spray formulations were prepared and the growing plants were sprayed at a spray volume of 60 gallons per acre and an application rate of 5 lb. per acre. Spray mixtures were prepared in the manner described above. For comparative purposes, plants were also sprayed at 60 gal. per acre with a spray mixture containing no growth regulant. Plant injury was again rated according to the schedule disclosed above.

Observations of growth regulant effects in both pre- and post-emergent tests were observed and recorded as follows:

    ______________________________________                                         Effect              Abbreviation in Tables                                     ______________________________________                                         Formative effect on new growth                                                                     F                                                          Epinasty            E                                                          Growth reduction    G                                                          Necrosis            N                                                          Non-emergence       K                                                          Chlorosis           C                                                          ______________________________________                                    

In the table below there are tabulated various observations of pre- and post-emergent herbicidal and growth regulant effects of the compounds disclosed above.

      EFFECTS OF COMPOUNDS ON PLANT LIFE Pre-emergent Effects Post-emergent      Effects  Compound Digitaria Celosia Bromus Setaria Raphanus Beta Setaria M      edicago Avena Raphanus Beta Lycopersicum  No. sanguinalis plumosa      inermis italica sativus vulgaris italica sativa sativa sativus vulgaris      esculentum Comments        3595 G1 K1G1 F3G2G2 F1 F2G1 G2 F2G1 G1 0 F2G2 F2 Increases fruit set      3600 F2G2 F2G1 F3G3 F1 F2G1 F2G1 0 F2G1 G1 0 F2G1 F2     " 3817 0 F2 F2      0 0 F1 G1 F1 0 F1 F2G1 F2     " 3818 F1 F2G1 F3G3 F2G2 F3G3 K4 G2F1 F3G2      F1G1 F3G2 F3G2 F2     " 3848 F1 F2G1 F3G2 F2G1 F1G1 F3G1 G2 F3G1 G1 G2F1      F3G2 F2     " 3923 0 F1 K2 0 0 F1 0 F1 0 0 F2 F1 3924 0 N4 K3 0 0 N4 0      F2G1 F1 F1 F3G1 F3 Increases fruit set 3925 G1 F1 K2F2 G2F1 F1 F2 F1 F2      F2G1 F2G1 F3G1 F3 Promotes tillering 3968 0 0 0 0 0 0 0 0 0 0 F1 F1 3969      0 N2 K2 0 0 0 0 0 0 0 0 0 3970 0 0 F1 0 0 0 0 0 0 0 F1 F1 3996 0 F1 F2      F1G1 F1 F2G1 G1F1 F3G3 F1 F2G1 F3G3 F3G3 3997 0 F1G1 F2 F1 0 F1 N1 F3G2      F1G1 F2G1 F3G2 F3G3 3998 F1 F1 F3G1 F2G1 F1 F2G1 F2G2 F1 G1 F1 F3G1 F3G3      3999 F1G1 F2G1 F3G3 F2G2 F1 F2G1 F1G1F3G3 F1G2 F2G1 F3G2 F3G3 4001 C1G1      F2 F1 0 F1 0 F1 0 0 F2G1 F3 4002 0 0 F1 0 0 0 0 F1 0 0 F2N1 F2 4003 0 F1      F2 0 0 F1 F2G1 F3G1 F2G3 F1G1 F3G2 F3G1 4004 F1G1 F1 F2G1 F2G2 F1G1 N4      F1G1 F3G2 F2G2 F3G3 F3G3 F3G3 4051 F3G2 F2G1 F3G3 F3G3 F2G1 F3G1 F3G2      F3G3 F3G2 F3G2 F3G2 F3G3 Increases fruit set 4088 0 0 0 0 0 0 0 0 0 0 F1      0 4089 0 0 0 0 0 F1 0 0 0 0 0 0 4090 0 0 F1 0 0 F1 0 F1G1 F1 F1G1 F1 F2      Increases fruit set and tillering 4091 0 F1 F1 0 0 F1 F1 F2G1 F1 F2 E3G3      F3 Increases fruit set 4092 0 F1 F2 0 0 F1 F2G2 F2G1 -- F2 N4 F3      Increases fruit set 4093 0 0 F1 0 0 F1 0 F2 F1G1 F1 F2 F2 Increases      fruit set and tillering 4094 0 0 F1 0 0 F1 0 F1 F1 0 F2 F1 4095 G1 F1 F2      0 F1 F1G1 F1G1 F3G2 F2G2 F2G1 F3G1 F3G2 Increases tillering, dark green      color 4098 0 0 0 0 0 0 0 0 0 0 F2N2 N1G1 4106 0 0 F1 F1 0 F2 0 F1 F1 0      F1 F1 Increases tillering 4146 0 N3G2 F2G1 F1G1 N3G2 F2G1 G2N1 0 0 F1 F2      F3 Increases fruit set 4147 0 N2G1 F1 0 N1G1 N4 0 0 0 0 F1 F1 4148 0 N4      N3G3 0 N3G3 N4 0 0 0 -- 0 0 4149 0 N3G3 N3G2 0 N4 N4 0 0 0 0 0 0 4154 0      0 F1 0 0 0 -- F1 0 F1G1 F1 F1 4155 G1 F2 F3G2 F2G2 F2G2 F2G1 F2G2 -- F1      F2G1 F2G1 F2 Increases fruit set 4156 F1G1 F1G1 F3G2 F3G2 F2G2 F1 F2G2      -- F1 F1G1 F2 F2 Increases fruit set 4157 F2G2 F2 F3G2 F3G2 F3G3 F2 F2G2      F2 F1 F2G1 F2 F2G1 Increases fruit set 4162 F1G1 F2G1 F3G1 F3G1 F2G1 F1      F2G2 F1G1 0 F1 F2 F3     " 4163 F3G3 F3G3 F3G3 F3G3 F3G3 F3G2 F2G1 F2      F2G1 F2G2 F2G1 F3 Increases fruit set and tillering 4164 F1 F2G2 F2G1 F1      F2G2 F2G1 F1 -- N1 F1 F1G1 N1F1 Increases fruit set 4165 F2 N4 F3G1 F2G2      F2G1 F3G1 F2G1 F3E2 0 F2G1 F3G3 F3     " 4166 F1 N4 F3G1 F2G1 N4 F2G2      F2G2 F3G2 F1 F2G2 F2G1 F2 Increases axillary growth 4167 F1 N3G2 F3G1 F1      N2 F1G1 F1 0 0 0 F1 F2 Increases fruit set 4168 F2G2 F3G2 F3G2 F2G2 F2G2      F1 F2G2 F3G1 F1 F1G1 F3G3 F3     " 4169 0 N3G3 F2G1 F1 N2G2 N3G3 F1 F1 0      F1 F2G1 F1     "  4170 F2G1 F2G2 F3G2 F2G2 F2G2 F3G2 F2G2 F1 F2G1 F1N1      F1 F3G1 Increases fruit set and tillering 4225 F3G2 F3G2 F3G3 F3G3 F3G3      F3G2 4226 F2G2 F1 F3G2 F3G2 F2G2 F2G2 4227 F1G1 F1G1 F2 F3G2 F2G1 F3G2      4228 0 0 F1 0 0 0

The use of many of the growth regulant compounds may be demonstrated by treatment of soybeans (soja max) to increase the number of seed pods and by treating tomato plants (Lycopersicum esculentum) to increase fruit set. In an illustrative experiment, Soja max (Evans variety) and Lycopersicum esculentum (Tiny Tim variety) were grown in 4-inch pots (one plant per pot) filled with greenhouse potting soil (2 parts good top soil, 11/2 parts builders sand, 11/2 parts peat, fertilized with 5 lb. of 12-12-6 fertilizer and 5 lb. of finely ground limestone per cu. yd.). Aqueous spray formulations were prepared and the potted plants were sprayed at a spray volume of 40 gal. per acre and at application rates of 16, 4, 1 and 1/4 oz. per acre. The spray mixtures were prepared by dissolving the proper amount of growth regulant compound in 15 ml. of acetone, adding 2 ml. of a solvent-emulsifier mixture consisting of 60 wt. percent of a commercial polyoxyethylated vegetable oil emulsifier (96 wt. percent active ingredient, Emulphor EL-719), 20 wt. percent xylene and 20 wt. percent deodorized kerosene, then bringing total volume up to 80 ml by addition of a 0.156 wt. percent aqueous solution of liquid non-ionic dispersant (90 wt. percent active trimethylnonyl polyethylene glycol ether, Tergitol TMN-10). Two replicates were sprayed at all application rates. For comparative purposes, plants were also sprayed at 40 gal./acre with water. The number of seed pods and of fruit as percentage of arithmetic mean of the numbers on untreated plants was observed within approximately three weeks after spray treatment and the results are tabulated below. The extent of growth regulatory effect on the plants was estimated on a scale of 0 to 10 and is also recorded in the following table:

    ______________________________________                                         GROWTH REGULATING EFFECTS ON TWO SPECIES                                       Soja mar                                                                               Pod                                                                            Count.sup.1                                                                    Percent in       Lycopersicum esculentum                                             Com-             Fruit Count.sup.1                                             parison   Growth Percent in                                                                              Growth                                 Com-          to        Regu-  Comparison                                                                              Regu-                                  pound Rate    Untreated lating to Untreated                                                                            lating                                 No.   (oz/A)  Plants    Effect.sup.2                                                                          Plants   Effect.sup.2                           ______________________________________                                         3595  16      147       8.5    171      5                                            4       140       3      186      2.5                                          1       124       1.5    186      0                                      3600  16      104       2.5    150      9                                            4       101       1      525      2                                            1       115       0      150      0                                      3779  16      138       4.5    147      3.5                                          4       121       1.5    74       0.5                                          1       121       1      59       0                                      3817  16      133       2      206      1                                            4       108       0.5    74       0                                            1       100       0      59       0                                      3818  16      104       2.5    132      0.5                                          4       104       1      132      0                                            1       100       0.5    88       0                                      3848  16      146       6      176      1.5                                          4       113       2.5    162      1.5                                          1       100       0.5    118      0                                      ______________________________________                                          .sup.1 Check = 100                                                             .sup.2 Greenhouse rating on scale of 0, no effect; 10, total kill.       

The information presented in tabular form herein will enable a worker in the art to make a selection from among the growth regulant compounds of the invention and to make some judgment with regard to application rates, depending upon the effect which is desired. It may be seen, for example, that total kills of some species of vegetation may occur at application rates as high as 5 to 10 lb. per acre, whereas beneficial effects may be observed on living plants at application rates of 1 lb. per acre or less.

The growth regulant compounds are usually applied in combination with inert carriers or diluents, as in aqueous sprays, granules and dust formulations in accordance with established practice in the art. An aqueous spray is usually prepared by mixing a wettable powder or emulsifiable concentrate formulation of a growth regulant with a relatively large amount of water to form a dispersion.

Wettable powders comprise intimate, finely divided mixtures of growth regulant compounds, inert solid carriers and surface active agents. The inert solid carrier is usually chosen from among the attapulgite clays, the kaolin clays, the montmorillonite clays, the diatomaceous earths, finely divided silica and purified silicates. Effective surfactants, which have wetting, penetrating and dispersing ability are usually present in a wettable powder formulation in proportions of from 0.5 to about 10 percent by weight. Among the surface active agents commonly used for this purpose are the sulfonated lignins, naphthalenesulfonates and condensed naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates and non-ionic surfactants such as products of condensation of ethylene oxide with alkylphenols.

Emulsifiable concentrates of the growth regulant compounds comprise in each instance, a solution of growth regulant compound in a liquid carrier which is a mixture of water-immiscible solvent and surfactants, including emulsifiers. Useful solvents include aromatic hydrocarbon solvents such as the xylenes, alkylnaphthalenes, petroleum distillates, terpene solvents, ether-alcohols and organic ester solvents. Suitable emulsifiers, dispersing and wetting agents may be selected from the same classes of products which are employed in formulating wettable powders.

In general, the growth regulants are seldom applied without the presence of a carrier or surfactant. However, direct application to plant seeds prior to planting may be accomplished in some instances by mixing powdered solid growth regulant with seed to obtain a substantially uniform coating which is very thin and comprises only one or two percent by weight or less, based on the weight of the seed. In most instances, however, a non-phytotoxic solvent, such as methanol is employed as a carrier to facilitate the uniform distribution of growth regulant on the surface of the seed.

When a compound is to be applied to the soil, as for a pre-emergence application, granular formulations are sometimes more convenient than sprays. A typical granular formation comprises the growth regulant compound dispersed on an inert carrier such as coarsely ground clay, or clay which has been converted to granules by treatment of a rolling bed of the powdered material with a small amount of liquid in a granulating drum. In the usual process for preparing granular formulations, a solution of the active compound is sprayed on the granules while they are being agitated in a suitable mixing apparatus, after which the granules are dried with a current of air during continued agitation. 

We claim:
 1. The method of regulating the growth of plants, including combating unwanted vegetation, comprises applying to the plants, either on seed, the soil or directly on the plants an effective amount of a compound having the general structural formula: ##STR5## in which Q₁, Q₂, Q₃ or Q₄ is N,X is --OH or --O--(C₁ -C₄ alkyl) and Y is H or X and Y together represent a bond between carbon and nitrogen atoms and R is H or one or two of the following substituents: --Br, --Cl, --F, --I, --CF₃, --CH₃, --NO₂ or --C.tbd.N or an agriculturally acceptable salt thereof.
 2. The method according to claim 1 in which Q₁ is N, X is --OH and Y and R are both --H.
 3. The method according to claim 1 in which Q₃ is N, X is --OH and Y and R are both --H.
 4. The method according to claim 1 in which Q₄ is N, X is --OCH₃, Y is --H and R is 4-fluoro.
 5. The method according to claim 1 in which Q₂ is N, X is --OCH₃ and Y and R are both --H.
 6. The method according to claim 1 in which Q₂ is N, X and Y together form a C--N bond and R is --H.
 7. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 3-chloro-2-methyl.
 8. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 4-fluoro.
 9. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 3,5-dichloro.
 10. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 3-trifluoromethyl.
 11. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 4-methyl.
 12. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 3-chloro.
 13. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 3,4-dimethyl.
 14. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 2,4-dimethyl.
 15. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 3-methyl.
 16. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 3,4-dichloro.
 17. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 4-chloro.
 18. The method according to claim 1 in which Q₄ is N, X is --OCH₃, Y is --H and R is 3-methyl.
 19. The method according to claim 1 in which Q₄ is N, X is --OCH₃, Y is --H and R is 3,4-dichloro.
 20. The method according to claim 1 in which Q₄ is N, X is --OCH₃, Y is --H and R is 3,5-dichloro.
 21. The method according to claim 1 in which Q₄ is N, X is --OCH₃, Y is --H and R is 3-trifluoromethyl.
 22. The method according to claim 1 in which Q₄ is N, X is --OCH₃, Y is --H and R is 3-chloro.
 23. The method according to claim 1 in which Q₁ is N, X and Y form a C--N bond and R is 4-fluoro.
 24. The method according to claim 1 in which Q₁ is N, X and Y form a C--N bond and R is 2-chloro.
 25. The method according to claim 1 in which Q₁ is N, X and Y form a C--N bond and R is 3-chloro-2-methyl.
 26. The method according to claim 1 in which Q₁ is N, X and Y form a C--N bond and R is 4-nitro.
 27. The method according to claim 1 in which Q₁ is N, X and Y form a C--N bond and R is --H.
 28. The method according to claim 1 in which Q₁ is N, X and Y form a C--N bond and R is 3-trifluoromethyl.
 29. The method according to claim 1 in which Q₁ is N, X and Y form a C--N bond and R is 4-methyl.
 30. The method according to claim 1 in which Q₁ is N, X and Y form a C--N bond and R is 3-chloro.
 31. The method according to claim 1 in which Q₁ is N, X and Y form a C--N bond and R is 3,4-dimethyl.
 32. The method according to claim 1 in which Q₁ is N, X and Y together form a C--N bond and R is 3-methyl.
 33. The method according to claim 1 in which Q₁ is N, X and Y together form a C--N bond and R is 3,4-dichloro.
 34. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 3-bromo.
 35. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 4-methyl.
 36. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 2-fluoro.
 37. The method according to claim 1 in which Q₁ is N, X and Y together form a C--N bond and R is 3-bromo.
 38. The method according to claim 1 in which Q₁ is N, X and Y together form a C--N bond and R is 4-trifluoromethyl.
 39. The method according to claim 1 in which Q₁ is N, X and Y together form a C--N bond and R is 2-fluoro.
 40. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 4-iodo.
 41. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 4-bromo.
 42. The method according to claim 1 in which Q₁ is N, X is --OH, Y is --H and R is 2,4-dichloro. 